Quantitative modelling of the role of hematopoietic stem- and progenitor niches in cell fate decisions

Supervisors: Prof Claus Nerlov and Dr Ed Morrissey

Many adult tissues are maintained by adult stem cells. These stem cells constantly produce cells of different types replacing old cells and regenerating tissues when damaged. The production of the correct complement of mature cell types requires that stem cells and downstream progenitors make appropriate cell fate decisions. These fate choices are regulated by the cells surrounding the stem- and progenitor cells, the so-called niche cells, However, while stem- and progenitor cells can be readily identified based on their functional properties, and purification of the associated niche cells after tissue dissociation or characterization of their molecular properties in situ is inherently challenging,

The aim of this project is to combine barcoded, high-throughput in situ hybridization with automated image analysis to directly gene expression profile the niche cells associated with hematopoietic stem- and progenitor cells cells in intact bone marrow tissue. The project will involve developing 3D image processing tools to extract data, allowing the cellular and molecular structure of niches to be identified. These data will be used to develop stochastic models to model cell fate choices of stem cells incorporating the information of their environment and develop bayesian tools to match the data to the models. 

This project is an interdisciplinary project and as such would suit someone with a quantitative background (Physics, Maths, Engineering or Computer Science) with an interest in biology.

References

  1. Vermeulen L*, Morrissey ER*, van der Heijden M, Nicholson AM, Sottoriva A, Buczacki S, Kemp R, Tavaré S and Winton DJ. 2013. Defining Stem Cell Dynamics in Models of Intestinal Tumor Initiation. Science 42:995-8.
  2. Drissen, R., N. Buza-Vidas, P. Woll, S. Thongjuea, A. Gambardella, A. Giustacchini, E. Mancini, A. Zriwil, M. Lutteropp, A. Grover, A. Mead, E. Sitnicka, S.E.W. Jacobsen and C. Nerlov. 2016. Distinct myeloid progenitor differentiation pathways identified through single cell RNA sequencing. Nat. Immunol. 17:666-76
  3. Buono, M., R. Facchini, S. Matsuoka, S. Thongjuea, D. Waithe, T. C. Luis, A. Giustacchini, P. Besmer, A. J. Mead, S.E.W. Jacobsen and C. Nerlov. 2016. A dynamic niche provides Kit ligand in a stage-specific manner to the earliest thymocyte progenitors. Nat. Cell. Biol. 18:157-167.

For further information please contact:  Prof Claus Nerlov